Carnitine is an obligatory cofactor for the oxidation of fat and hence for the generation of ketosis. Our previous studies in human fasting have shown highly significant changes in plasma and urine carnitine and acylcarnitines which coordinated with increasing ketoacid production. Normal weight and obese subjects showed highly divergent rates of development of ketosis relative to changes in carnitine metabolites. The present proposal intends to explore and define further the relationship between carnitine metabolism and ketosis by: developing and refining methods for the identification and quantitation of individual urine and plasma acylcarnitines; refining analytical methods for trimethyllysine, a carnitine precursor, and for dicarboxylic acid products of fat oxidation; applying such analyses to the urine and plasma of fasting subjects and of subjects with diabetic ketosis before and after insulin treatment; determining the relationship between carnitine metabolites and ketoacids during acute stimulation of ketosis with glucagon in insulin-deficient diabetics; employing somatostatin variously coupled with glucagon and insulin infusion to reproduce acutely the hormonal milieu of fasting, thereby allowing assessment islet hormone effects on carnitine and its metabolites; investigating the role of carnitine in the retardation of fasting ketosis observed in subjects with obesity. We anticipate that these studies will enhance our understanding of the abnormal patterns of lipid oxidation in diabetes mellitus and obesity.